Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality in the United States. While smoking is clearly the main environmental factor leading to COPD, only a fraction of smokers develop clinically significant COPD, and genetic determinants influence this variability. The availability of large-scale DNA sequencing at low cost has made whole exome sequencing a feasible study design, rather than limiting analysis to candidate genes. Whole exome sequencing has been successful in the identification of rare genetic determinants of monogenic syndromes, and it has the potential to identify rare nonsynonymous SNPs influencing the variable development of COPD. Since subjects with severe, early-onset COPD may be enriched for COPD genetic determinants, we will focus our gene discovery efforts on two unique family-based resources which have included large numbers of severe, early-onset COPD probands: the Boston Early-Onset COPD Study and the International COPD Genetics Network. A total of 700 subjects from these two study populations will undergo whole exome sequencing and rare variant analysis using family-based and case- control methods. We will replicate these rare variant associations in families ascertained through probands with later-onset COPD in the International COPD Genetics Network. Finally we will assess the impact of genes with rare variant associations in subjects with specific chest CT-defined subtypes of COPD and in African Americans in the COPDGene Study. Our overall hypothesis is that rare, functional genetic variants influence the development of COPD. By focusing on subjects with a severe, early-onset form of a complex disease, the likelihood of finding valid susceptibility genes will be enhanced. Our step-wise analytical strateg will assess the impact of these rare variant associations in later-onset COPD, in African Americans with COPD, and in specific imaging subtypes of COPD. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary disease (COPD) is a major public health problem. DNA sequencing of all of the coding regions (exons) for proteins in the human genome will be performed in families with severe, early-onset COPD. This whole exome sequencing as well as follow-up candidate DNA sequencing in other subjects will identify novel, rare genetic causes of COPD. Identification of these genetic determinants may lead to new insights into the biological mechanisms causing COPD and suggest new pathways for treatment.